Graphic abstract. credit: Molecular cell (2022). DOI: 10.1016 / j.molcel.2022.05.031
Serotonin (5-HT) is one of the major neurotransmitters in the human central and peripheral nervous system. It helps regulate appetite, memory, cognition and mood through serotonin receptors (5-HTR).
A group of international scientists recently made a breakthrough in understanding the structure and function of serotonin receptors. This is the first time researchers have reported the structures of 5-HT4, 5-HT6 and 5-HT7 receptors and have resolved the structures of all 12 subtypes of 5-HT receptors.
The study is published online at Molecular cell on June 16.
Researchers led by H. Eric Xu of the Shanghai Institute of Matter (SIMM) of the Chinese Academy of Sciences, in collaboration with researchers from Zhejiang University and the University of Copenhagen, systematically uncovered the structural basis for recognizing serotonin receptor subtypes from low molecular weight ligands 5 -HT and 5-CT. They also elucidate the molecular mechanism for the selective binding of Gs and Gi proteins by serotonin receptors.
The serotonin receptor family is one of the most complex subfamilies in the G-protein-coupled receptor (GPCR) superfamily and contains 12 subtypes. Different subtypes of receptors play different physiological roles in the human body and are combined with different types of G proteins. Among them, 5-HT4, 5-HT6 and 5-HT7 receptors are mainly bound to downstream Gs proteins, and 5-HT1 and 5-HT5 receptors are mainly bound to downstream Gi proteins.
By structurally comparing these three Gs-linked serotonin receptors with Gi / o-linked serotonin receptors and with 19 additional Gs- and Gi / o-linked class A receptor structures, the team uncovered a class-wide G protein selectivity mechanism that uses TM5 and TM6 switches.
“These findings improve the fundamental understanding of how serotonin receptors, the largest subfamily of class A GPCRs activated by the same endogenous ligand, generate their wide variety of cellular responses,” said Sue, the study’s author.
In addition, these structural insights into ligand recognition provide the basis for a rational structural-based drug design targeting 5-HT4, 5-HT6, and 5-HT7 receptors. These insights also help to clarify how to achieve ligand selectivity within a complex serotonergic system.
The achievement not only revealed the molecular mechanism of selective binding of G-proteins from GPCRs of class A, but also filled the last gap in the structural analysis of 5-HT family receptors, according to researchers.
These systematic studies of serotonin receptors have greatly enriched our understanding of the structure and function of the serotonin system. Because depression, schizophrenia, and migraine may be associated with serotonin, this study may also contribute to the treatment of these conditions.
Researchers discover how lipids and water molecules regulate 5-HT receptors More information: Sijie Huang et al, GPCRs control Gi and Gs selectivity through TM5-TM6 switches, as revealed by serotonin receptor structures, Molecular cell (2022). DOI: 10.1016 / j.molcel.2022.05.031 Provided by the Chinese Academy of Sciences
Citation: Scientists make a breakthrough in the understanding of serotonin receptors (2022, June 17), derived on June 17, 2022 from
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